Our program's multidisciplinary research activities are carried out at several NIH-sponsored laboratories and clinics in malaria-endemic regions of Mali and Cambodia, where we investigate four subject areas: (1) the molecular mechanism by which sickle-cell trait (hemoglobin S) confers protection to Plasmodium falciparum malaria; (2) the parasite and host factors that influence the rate of P. falciparum parasite clearance in patients treated with the antimalarial drug artemisinin; (3) the molecular mechanisms of P. falciparum resistance to frontline antimalarial drugs, including artemisinin and piperaquine; and (4) the role of Anopheles mosquito vectors in the spread of multidrug-resistant P. falciparum parasites. In each of these areas we seek research advances that improve our knowledge of disease processes and drug-resistance mechanisms in patients with malaria, with the ultimate goal of developing new antimalarial therapeutics, vaccines, and transmission-blocking interventions to prevent infection, illness, and death.